ONC: Chemotherapy (2007)

Citation:
 
Study Design:
Class:
- Click here for explanation of classification scheme.
Quality Rating:
Research Purpose:
To determine whether parenteral nutrition support (PNS) sustains patients through chemoradiation therapy (CRT) and what influence (if any) it has on the associated morbidity, mortality, and efficacy of combination CRT and subsequent surgery.
Inclusion Criteria:
  • One of the first 45 subjects enrolled in a phase I/II trial evaluating a combined induction CRT regimen
  • Confirmed histologic diagnosis of adenocarcinoma or squamous cell carcinoma of the esophagus or gastroesophageal junction
  • No prior therapy
  • Performance status of Eastern Cooperative Oncology Group (ECOG) 0-2
  • Complete clinical and radiologic evaluations of the abdomen with a barium series and a CT scan of the chest
  • Acceptable candidate for surgical resection (esophagectomy)
Exclusion Criteria:
None listed
Description of Study Protocol:

Recruitment   Not described

 

Design  Patients involved in a phase I/II chemoradiation induction protocol were grouped according to their need for parenteral nutrition support via retrospective chart review.

Medical regimen:

  • All patients received combined chemoradiation therapy over a period of either 28 days (initial 17 patients) or 21 days in the hospital.
    • Chemotherapy regimen involved a three-drug protocol:
      • 5-FU at a dose of 250-350 mg/m2/day by continuous IV infusion in a dose escalation pattern over 21-28 days
      • cisplatin at a dose of 20 mg/m2 by IV infusion on the first and last 5 days of the schedule
      • interferon alpha-2b (IFN-alpha) at a dose of 3MU/m2/day subcutaneously three times a week for 21-28 days
    • A double fractionated radiation schedule was administered for a total of 4500 cGy at 150 cGy twice daily
    • CRT was modified or stopped according to the dose-limiting toxicity criterion defined:
      • 5-FU infusion was stopped for grade III mucositis or diarrhea persistent for at least 2 days which was not responsive to palliative treatment measures.
      • If absolute neutrophil count <1000, 5-FU dose was reduced 25%
      • If absolute neutrophil count <500, 5-FU was held and granulocyte colony-stimulating factor at a daily dose of 300 µg/kg was given subcutaneously. When the absolute neutrophil count rose to >1000, 5-FU was restarted at 75% of the full dose
      • For platelets <50,000 cells/µL, 5-FU was withheld until platelets rose to >100,000 cells/µL and then restarted at 75% of full dose.
  • Approximately 3 weeks after the completion of induction CRT, resectable patients underwent surgical exploration, and esophageal resection was undertaken with surgical approach at the discretion of the surgeon.
Parenteral Nutrition Support Regimen
  • During the period of induction, daily calorie counts were obtained for all patients.
  • When daily caloric intake was <1000 kcal/day for 2 consecutive days PNS was initiated. The decision to initiate PNS was made by the treating physician and the nutrition support service.
  • Parenteral nutrition was designed to provide total nonprotein caloric intake of 30-35 kcal/kg/day with glucose (70%) and fat (30%) as the caloric sources. A total of 1-1.5 g/kg/day protein from an amino acid source was administered, and the forumulation was supplemented with electrolytes, vitamins and minerals.
  • Parenteral nutrition was continued at home, if needed, until adequate oral intake was established or until surgery.
  • A retrospective chart review classified patients according to their need for parenteral nutrition:
    • parenteral nutrition support (> 8 days)
    • no parenteral nutrition support
      • Three patients received parenteral nutrition support for 3, 5, and 7 days respectively.
      • Patients were encouraged to take high calorie oral supplements (variable compliance)

 

Blinding used (if applicable)  Not discussed

 

Intervention (if applicable)   None

 

Statistical Analysis

  • Categorical variables were analyzed by X2 or Fisher's exact test.
  • Continuous variables were analyzed by Student's t test.
  • All statistical analyses were two tailed and a value of <0.05 was considered statistically significant.

 

Data Collection Summary:

Timing of Measurements: NA

 

Dependent Variables

  • Chemotherapy dose administered: amount of chemotherapy administered as a percentage of the estimated dose administered
  • Radiation dose administered: amount of radiation administered as a percentage of the estimated dose
  • Morbidity of CRT
  • Response rates
    • Complete: no pathological evidence of the tumor
    • Major: presence of microscopic disease only on pathological examination
    • No response: presence of gross residual disease
  • Surgical outcome

Independent Variables

  • Parenteral nutrition support

Control Variables: NA

 

Description of Actual Data Sample:

 

Initial N:

  • 45 consecutive patients enrolled in a phase I/II trial
    • PNS (n=30)
      • 25 males
      • 5 females
    • No PNS (n=15)
      • 12 males
      • 3 females

Attrition (final N):

  • For CRT schedule, dosage, response rates, and toxicity: n=45
  • For post surgical complications: n=40
    • 3 CRT related deaths (2 in PNS group, 1 in no PNS group)
    • 2 patients with progression of their disease

Age:

  • PNS
    • Median age: 66.5 yr
    • Range: 37-77 yr
  • No PNS
    • Median age: 68.5 yr
    • Range 30-75 yr

Ethnicity:  Not described

Other relevant demographics:

  • Site
    • PNS
      • Middle 1/3: n=4
      • Distal/GE: n=26
    • No PNS
      • Middle 1/3: n=3
      • Distal/GE: n=12

 

  • Pathology
    • Adenocarcinoma
      • PNS: n=19
      • No PNS: n=10
    • Squamous cell carcinoma
      • PNS: n=8
      • No PNS: n=4
    • Adenosquamous cell carcinoma
      • PNS: n=3
      • No PNS: n=1

 

  • Surgical procedure
    • Transhiatal
      • PNS: n=25
      • No PNS: n=11
    • Transthoracic
      • PNS: n=2
      • No PNS: n=2

Anthropometrics (e.g., were groups same or different on important measures)

Location:

University of Pittsburgh Medical Center, PA

 

Summary of Results:
Comparison of Nutritional Parameters Before and After CRT

Parameter       

PNS  

p value

No PNS

p value

Weight (kg)

 




 

Pre-CRT

 83.3

 

 78.3

 

Post-CRT

 80.0  

 0.04

 78.3  

 0.91
Wt/ideal wt  
     
 Pre-CRT  1.28   1.17
 
 Post-CRT 1.22
0.01
1.17
0.95
Albumin
       
 Pre-CRT  3.95   3.83
 
 Post-CRT 3.67
0.009
3.55 
0.06
Hemoglobin (g/dL)
       
 Pre-CRT 13.8
  13.8
 
Post-CRT 10.8 <0.000 10.8 <0.000

P values compare the pre-CRT value withthe respective post-CRT value.

1. Pre- and post-CRT comparisons of nutritional parameters (body wt, ratio of body wt to ideal body wt, serum albumin and hemoglobin) indicated significant decreases in wt, body wt-to-ideal body wt ratio, and albumin levels in patients receiving PNS.

2. Both groups showed a significant decrease in hemoglobin levels before CRT vs after CRT which was related to CRT toxicity.


Chemoradiation Therapy Schedule, Dosage and Response Rates

  PNS No PNS p value
  (n=30) (n=15)  
Chemotherapy schedule      
Completed 8 2  
Modified 19 8  
Stopped 3 5 0.13
% of estimated dose admin      
5-FU 86.4 68.8 0.02
IFN-alpha 95.4 79.8 0.05
CDDP 90.8 78.2 0.05
XRT 97.8 80.1 0.05
Response Rates*      
Complete 7 (23) 3 (20)  
Major 16 (53) 7 (47)  
No repsonse 4 (14) 3 (20) 0.8

CDDP (cisplatin), XRT (radiation therapy)
*Values are number of patients with percentage in parentheses

1. The group receiving PNS received a significantly higher dose of 5-FU, cisplatin and IFN-alpha.

2. The percentage of estimated radiation dose administered was significantly higher in the group receiving PNS.

3. The response rates were comparable between the two groups.


Grade III/IV Chemotherapy-Related Toxicity

  PNS No PNS P value
Toxicity (n=30) (n=15)  
Hematological 28 (93.3) 13 (86.6) 0.59
Anemia 2 (6.6) 4 (26.6) 0.15
Neutropenia 4 (13.3) 6 (40) 0.06
Thrombocytopenia 9 (30) 1 (6.6) 0.12
Gastrointestinal 17 (56.6) 5 (33.3) 0.20
Liver Function Abnormalities 1 (3.3) 1 (6.7) 1.0
Metabolic Abnormalities 3 (10) 2 (13.3) 1.0
CRT stay (days)* 31.2 34.3 0.26

Values are number of patients with percentage in parentheses.
*Values are means.

1. CRT-related toxicity was significnt, primarily hematologic and gastrointestinal, and was managed with appropriate dose modifications and supportive therapy.

2. CRT toxicities and CRT-related hospital stay were comparable between the two groups.


Postsurgical Complications

  PNS No PNS P values
  (n=27) (n=13)  
Complications* 14 (51.8) 8 (61.5) 0.73
Pneumothorax 14 7  
Vocal cord paralysis 1 1  
Leak 3 1  
Chylothorax 3 1  
Wound Infection 4 1  
Chest Infection 9 2  
Cardiac 5 3  
Miscellaneous 5 4  
Mortality* 2 (7.4) 1 (7.6) 1.00
ICU Stay (days)§ 4.0 4.3 0.82
Hospital Stay (days)§ 22.5 19.6 0.63

*Values are number of patients with percentage in parentheses
§ Values are means.

1. There were no significant differences in mortality, length of stay in the ICU and hospital for patients undergoing surgery between the two groups.

Other Findings

In the PNS group, the median duration of PNS was 20 days with a range of 10-45 days.

 

Author Conclusion:
Although early and prolonged PNS facilitated administration of complete CRT doses, no benefit was derived from the administration of more CRT in the present regimen. The utility of PNS in this setting is unclear and, until further clarified, should not be applied routinely to this subset of patients.
Funding Source:
University/Hospital: University of Pittsburg
Reviewer Comments:
Unclear why authors included patients who received nutrition support in the "no PNS" group.

Description of nutritional status at onset of induction CRT lacking. Degree of malnutrition not captured accurately with serum albumin and current weight. Would like to have seen baseline assessment percent weight loss prior to initation of therapy. As a means for assessing nutritional status, serum albumin is not particularly sensitive to short term changes in feeding and levels are affected by non-nutritional factors.

No description of caloric intake during induction therapy of either group other than to describe the circumstance of when PNS was initiated. No description of the percentage of the nutritional regimen delivered through PNS or supplements during induction therapy. No description of parameters used to discontinue PNS. If >1000 kcal/day, patients could still be receiving suboptimal amount of kcal.

No discussion of any complications related to PNS e.g. infection, metabolic abnormalities. etc.

Assumed that this study was conducted at single center vs multiple sites.
Quality Criteria Checklist: Primary Research
Relevance Questions
  1. Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies) Yes
  1. Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies) Yes
  2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? Yes
  2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? Yes
  3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice? Yes
  3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice? Yes
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies) Yes
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies) Yes
 
Validity Questions
  1. Was the research question clearly stated? Yes
1. Was the research question clearly stated? Yes
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? Yes
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? Yes
  1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? Yes
  1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? Yes
  1.3. Were the target population and setting specified? Yes
  1.3. Were the target population and setting specified? Yes
  2. Was the selection of study subjects/patients free from bias? Yes
2. Was the selection of study subjects/patients free from bias? Yes
  2.1. Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study? Yes
  2.1. Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study? Yes
  2.2. Were criteria applied equally to all study groups? Yes
  2.2. Were criteria applied equally to all study groups? Yes
  2.3. Were health, demographics, and other characteristics of subjects described? Yes
  2.3. Were health, demographics, and other characteristics of subjects described? Yes
  2.4. Were the subjects/patients a representative sample of the relevant population? Yes
  2.4. Were the subjects/patients a representative sample of the relevant population? Yes
  3. Were study groups comparable? ???
3. Were study groups comparable? ???
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) ???
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) ???
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? Yes
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? Yes
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) Yes
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) Yes
  3.4. If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis? N/A
  3.4. If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis? N/A
  3.5. If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.) N/A
  3.5. If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.) N/A
  3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? N/A
  3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? N/A
  4. Was method of handling withdrawals described? Yes
4. Was method of handling withdrawals described? Yes
  4.1. Were follow-up methods described and the same for all groups? Yes
  4.1. Were follow-up methods described and the same for all groups? Yes
  4.2. Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.) Yes
  4.2. Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.) Yes
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? Yes
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? Yes
  4.4. Were reasons for withdrawals similar across groups? Yes
  4.4. Were reasons for withdrawals similar across groups? Yes
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? N/A
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? N/A
  5. Was blinding used to prevent introduction of bias? Yes
5. Was blinding used to prevent introduction of bias? Yes
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? No
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? No
  5.2. Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.) Yes
  5.2. Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.) Yes
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? N/A
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? N/A
  5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status? N/A
  5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status? N/A
  5.5. In diagnostic study, were test results blinded to patient history and other test results? N/A
  5.5. In diagnostic study, were test results blinded to patient history and other test results? N/A
  6. Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described? No
6. Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described? No
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied? Yes
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied? Yes
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? N/A
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? N/A
  6.3. Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? ???
  6.3. Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? ???
  6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? No
  6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? No
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? Yes
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? Yes
  6.6. Were extra or unplanned treatments described? Yes
  6.6. Were extra or unplanned treatments described? Yes
  6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? Yes
  6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? Yes
  6.8. In diagnostic study, were details of test administration and replication sufficient? N/A
  6.8. In diagnostic study, were details of test administration and replication sufficient? N/A
  7. Were outcomes clearly defined and the measurements valid and reliable? Yes
7. Were outcomes clearly defined and the measurements valid and reliable? Yes
  7.1. Were primary and secondary endpoints described and relevant to the question? Yes
  7.1. Were primary and secondary endpoints described and relevant to the question? Yes
  7.2. Were nutrition measures appropriate to question and outcomes of concern? No
  7.2. Were nutrition measures appropriate to question and outcomes of concern? No
  7.3. Was the period of follow-up long enough for important outcome(s) to occur? ???
  7.3. Was the period of follow-up long enough for important outcome(s) to occur? ???
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? Yes
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? Yes
  7.5. Was the measurement of effect at an appropriate level of precision? Yes
  7.5. Was the measurement of effect at an appropriate level of precision? Yes
  7.6. Were other factors accounted for (measured) that could affect outcomes? Yes
  7.6. Were other factors accounted for (measured) that could affect outcomes? Yes
  7.7. Were the measurements conducted consistently across groups? Yes
  7.7. Were the measurements conducted consistently across groups? Yes
  8. Was the statistical analysis appropriate for the study design and type of outcome indicators? Yes
8. Was the statistical analysis appropriate for the study design and type of outcome indicators? Yes
  8.1. Were statistical analyses adequately described and the results reported appropriately? Yes
  8.1. Were statistical analyses adequately described and the results reported appropriately? Yes
  8.2. Were correct statistical tests used and assumptions of test not violated? Yes
  8.2. Were correct statistical tests used and assumptions of test not violated? Yes
  8.3. Were statistics reported with levels of significance and/or confidence intervals? Yes
  8.3. Were statistics reported with levels of significance and/or confidence intervals? Yes
  8.4. Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)? ???
  8.4. Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)? ???
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? No
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? No
  8.6. Was clinical significance as well as statistical significance reported? Yes
  8.6. Was clinical significance as well as statistical significance reported? Yes
  8.7. If negative findings, was a power calculation reported to address type 2 error? No
  8.7. If negative findings, was a power calculation reported to address type 2 error? No
  9. Are conclusions supported by results with biases and limitations taken into consideration? Yes
9. Are conclusions supported by results with biases and limitations taken into consideration? Yes
  9.1. Is there a discussion of findings? Yes
  9.1. Is there a discussion of findings? Yes
  9.2. Are biases and study limitations identified and discussed? Yes
  9.2. Are biases and study limitations identified and discussed? Yes
  10. Is bias due to study's funding or sponsorship unlikely? Yes
10. Is bias due to study's funding or sponsorship unlikely? Yes
  10.1. Were sources of funding and investigators' affiliations described? No
  10.1. Were sources of funding and investigators' affiliations described? No
  10.2. Was the study free from apparent conflict of interest? Yes
  10.2. Was the study free from apparent conflict of interest? Yes